Our research efforts in this program are focused on the elucidation of structure-taste relationships among peptide derived molecules. To this end we have employed synthesis, spectroscopy, computer simulations and, where applicable, x-ray diffraction studies of constrained molecules. We discovered a novel class of sweeteners based on the retro-inverso peptidomimetic modification. Using these retroamides and their corresponding stereoisomeric dipeptide amide analogs we have developed a model to explain the sweet taste. Stereoisomeric retro and dipeptide amides were studied by NMR and flexible geometry energy minimizations. It was shown that the sweet molecules prefer and "L shape" for the zwitterionic ring and the large hydrophobic group. The N, (-L-aspartyl)- N', (tetramtheylcyclopentanoyl) (R and S)-diaminoethane molecules cocrystallize. The x-ray structures show that these compounds prefer the "L shape" in the solid state. We have also related the x-ray structure of aspartame to our model. Other peptide-like molecules synthesized in our laboratories have been examined by NMR and computer simulations to ascertain their preferred structures. The taste properties of these molecules agree with our proposed model. We now intend to extend our studies to probe the structure of the taste receptor by preparing various series of constrained molecules with different geometries from those prepared to date. These molecules include other retroamides and retro modified tripeptides. Additional target molecules incorporate 1- aminocycloalkane carboxylic acid residues. In this manner, we hope to develop a precise understanding of structure-taste relationships and to design novel, safe and stable tastants.